6,7-methylene-9beta,10alpha-steroids and methods for the preparation thereof



United States Patent 3,539,599 6,7-METHYLENE-9fl,loot-STEROIDS AND METHODS FOR THE PREPARATION THEREOF Harmen van Kamp, Weesp, Netherlands, assignor, by

mesne assignments, to US. Philips Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Jan. 29, 1968, Ser. No. 701,051 Claims priority, application Great Britain, Feb. 2, 1967, 5,028/ 67 Int. Cl. C07c 169/20, 169/34 US. Cl. 260-3973 Claims ABSTRACT OF THE DISCLOSURE 6,7-methylene-95,10a steroids of the androstane or pregnane series are prepared. Examples are 6a-fluoro-6B, 73 methylene-17fl-hydroxy-9B,10u-androst-4-en-3- or 17- acetate and 6fl,7;6-methy1ene-9,B,lOu-pregna 1,4-diene-3, -dione.

The invention relates to new 6,7-methylene-9p,10asteroids of the formula in which formula R represents a single or double bond between the carbon atoms 1 and 2,

R is a hydrogen, a chloro or a fluoro atom, and

R is a hydroxyl group, an esterified hydroxyl group, an

acetyl group or a -CHOHCH group.

The pregnane compounds of the invention are progestational agents having an influence on the pituitary. In particular the pregnane compounds wherein R is a halogen have a strong inhibiting action on the gonadotropins. The compounds of the pregnane series Where R is a hydrogen atom have in addition to the activities mentioned above, an anti-estrogenic activity.

The androstane compounds of the invention exhibit an anabolic-androgenic activity.

The inhibition of the pituitary activity may be useful in cases of hyperproduction of gonadotropins and further in the treatment of menopausal patientsor treatment of puberas praecox.

The compounds of the invention wherein R is a -CHOH-CH group may be used as starting material for the preparation of compounds with hormonal activities.

The hydrogen atoms or methyl groups at the carbon atoms 8, 9, 10, 13, and 14 of the compounds according to the invention have the same stereochemical configuration as the corresponding hydrogen atoms and methyl groups in dihydro-isolumisterone.

Castells et al., Proc. of the Chemical Society, 1958, p. 7, have shown that dihydro-isolumisterone has the configuration 818,95,10ct-methyl,l35-methyl,14a.

The novel steroids of the invention are indicated as 9 3,10a-steroids to indicate at which carbon atoms (9 and 10) the configuration deviates from the normal steroids and in which sense (95,100; in distinction to the 9a,10,8- configuration of the normal steroids).

The methylene group connected to carbon atoms 6 and 7 and the substituents R at carbon atom 17 have the ice fl-configuration, whereas the substituent R occupies the a-position.

When R represents an esterified hydroxyl group, then the acyl part of said esterified hydroxyl group may contain from 1-20 carbon atoms and is preferably the acyl group of a saturated or unsaturated aliphatic mono-, dior tricarboxylic acid, aromatic carboxylic acid, mixed aliphatic-aromatic carboxylic acid or a saturated or unsaturted alicylicor mixed aliphatic-alicylclic monocarboxylic acid, especially those having from 1-16 carbon atoms. Examples of acyloxy groups are: formoxy, acetoxy, propionoxy-, butyroxy-, acyloxy groups of oleic acid, palmitic acid, caproic acid, pivalic acid, succinic acid, undecyloic acid, malonic acid, citric acid, hexahydrobenoic acid, phenylacetic acid, fl-cyclopentyl-propionic acid, fi-cyclohexylpropionic acid.

Preferred compounds of the underlying invention are: 66,7,8-methylene-913,1()u-pregn-4-en-3,ZO-dion, 6fl,7 3-methylene-9fi, IOa-pregna-1,4-diene-3,20-dion, 6fl,7B-methylene-20Bhydroxy-9fl,10a-pregn-4-en-3-on, 6:1-chloro,6 3,7,B-methylene-9;8,10a pregna-1,4-dien-3-20- dion, 6a-chloro-6,8,7B-methylene-9fl,l0u-pregn-4-en-3,20-dion, 6,B-7/3-methylene-17fl-hydroxy-9B,10a-androst-4-en-3-on, 65,7,8-methylene-17fi-hydroxy-9B,10a androst-4-en-3-on 17-phenyl-propionate,

6a-fiuoro-6BJB-methylene-17B hydroxy-9fl,10a-androst- 4-en-3-on 17-acetate,

6wchloro-6fi,7fi-methylene-17 3-hydroxy-913,10a androst- 4-en-3-one, and

6a-chloro-65,7B methylene 17;8-hydroxy 9fl,10a-androsta-1,4-dien-3-one 17 acetate.

Other compounds of the invention are:

618,7;8-methylene-17B hydroxy-9fl,10u androsta-1,4- dien-3-on, 6,9,7/3-methylene-17,8-hydroxy-9fi,loot-androsta- 1,4dien-3-0n 17-acetate and the corresponding 17-formate-, 18-propionate-, 17-butyrate-, 17-enanthate-, 17- pivalate-, 17-undecylenate, 17-caproate-, 17-palimitate-, 17-stearateand 17-phenylpropionate esters,

6B-7B-methylene-l7/3-hydroxy-9B,10a androst-4-en-3- one 17-acetate and the corresponding 17-formate, 17- propionate, l7-butyrate-, 17-enanthate-, 17-pivalate-, 17- undecylate-, 17-caproate-, 17-palmitate and 17-stearate esters,

60t-fil10IO-6 3,7/3 methylene-9fi,l0a pregn-4-en-3,20- dion, 6 a-fluoro-6 [3,7 B-methy1ene-9p, 1 ()u-pregna- 1 ,4-dien-3, 20-dion, 6a-fluoro-6/3,7;3 methylene-17,8-hydroxy-9B,10a androsta-1,4-diene-3-one 17-acetate and the corresponding 17-formate-, 17-pripionate-, 17-butyrate-, 17-enanthate-, 17-pivalate-, 17-undecy1enate-, 17-caproate-, 17-palmitate-, 17-stearateand 17-phenylpropionate esters,

6a-fiuoro-6flJ 3 methylene 17/8-hydroxy-9B,10u-androsta-4-en-3-on 17-formate and the corresponding 17- propionate-, 17-butyrate-, l7-enanthate-, 17-privalate-, l7- undecylenate-, l7-caproate-, 17-palmitate-, 17-stearate and 17-phenylpropi0nate esters.

6u-fluoro-6B,7 3-methylene 17,6-hydroxy 9 3,10a-androsta-l,4-dien-3-on,

6oc-Chl010 6,8,7/3 methylene-17fi-hydroxy-9fi, IOa-androsta-4-en-3-on 17-acetate and the corresponding 17- formate, l7-propionate-, 17-butyrate-, 17-enanthate-, 17- pivalate-, 17-undecylenate-, 17-caproate-, 17-palmitate-, 17-stearateand 17-pheny1propionate esters,

6u-Chl0I0-6/3, 7fi-methylene-17,8-hydroxy-9p, IOa-androsta-1,4-dien-3-one 17-formate and the corresponding 17 propionate, 17-butyrate-, 17-enanthate-, 17-pivalate-, 17-undecylenate-, 17-caproate-, 17-palmitate-, l7-stearateand 17-phenylpropionate esters.

The compounds according to the invention may be prepared according to methods known per se for the preparation of analogous compounds.

In particular the methods of producing the new 96, lOot-steroids are characterized in that compounds of the general formula:

CH3 CH3 i CH2 R R represents a single or double bond between carbon atoms 1 and 2,

R represents a hydrogen, chloro or fluoro atom, and

R represents a hydroxy, acetyl, esterified hydroxyl or a -CHOH--CH group,

are produced in that (a) A compound of the formula I I I I I R represents a single or atoms 1 and 2,

R represents a chloro or fluoro atom, and

R represents a hydroxyl, acetyl, esterified hydroxyl or a CHOHCH group,

is reacted with dimethylsulfoxoniummethylide to produce the corresponding 3-keto-4-dehydro-6ot-halogeno-6/3Jfimethylene-95,wot-steroid.

(b) A compound of the formula in which formula double bond between carbon CH3 CH3 i 17 i I l i 'r/ in which formula (c) A compound of the formula in Which formula R represents a hydrogen, chloro or fluoro atom, and R represents a hydroxyl, acetyl, esterified hydroxyl or a -CHOHCH group,

is dehydrogenated to introduce a A -double bond.

((1) A compound of the formula CHa in which formula R represents a single or double bond between carbon atoms 1 and 2, and R represents a hydrogen, chloro or fluoro atom,

is esterified to produce the corresponding 17-esterified hydroxyl group.

(e) A compound of the formula in which formula R represents a single or double bond between carbon atoms 1 and 2, and

R represents a hydrogen, chloro or fluoro atom is oxidized to produce a 17,8-COCH compound.

The methods set forth above under (b) have been described in part in literature (Krakowen, G. W. and Van Dine, H. A., The Synthesis of Steriodal Cycl0pr0pan0 Ketones, Journal of Organic Chmistry, 31, 3467-3473 (1966) and Wepsong, N. H., Edwars, J. A. and Fried, J. H., Tetrahydron Letters, 1966, 1841).

The dimethylsulfoxonium reagent (methods (a) and (b)) is prepared by reaction of trimethylsulfoxonium iodide with a base e.g. alkali hydrides or hydroxides in the presence of a solvent e.g. dimethylsulfoxide. The reaction for the preparation of the inventive compounds according to the methods (a) and (b) is carried out in the presence of a solvent at a reaction temperature which may be varied between 0 and C. but which is preferably between 1530 C. Suitable solvents are dimethylsulfoxide, ethers such as diethylether, tetrahydrofuran, dioxan or mixtures thereof.

The methods enumerated above under (c)(e) inclusive have been described in literature in more detail. A survey thereof follows below.

INTRODUCTION OF A A -DOUBLE BOND (1) By direct l-dehydrogenation with iodine pentoxide;

(2) By direct l-dehydrogenation with selenium dioxide, J. H. Fried et al., J. Am. Chem. Soc., 81, 1235 (1959); H. Bouwers et al., J. Am Chem. Soc. 81, 5991 (1959);

(3) By direct l-dehydrogenation with 2,3-dichloro-5, 6-dicyanobenzoquinone, D. Burn, et al., Proc. Chem. Soc., 1960, 14;

(4) By direct l-dehydrogenation with lead tetraacetate, R. L. Clarks, J. Am. Chem. Soc., 77, 661 (1959); R. Joly, Bull. Soc., 366 (1958);

(5) By microbiological l-dehydrogenation, A. Nobile et al., J. Am. Chem. Soc., 77, 4184 (1955).

ESTERIFICATION OF A l7-HYDROXY GROUP The esterification may be carried out with the previously mentioned acids, their acid anhydrides or acid halides, in the presence of a catalyst such as p-toluenesulphonic acid or pyridine.

OXIDATION OF A ZO-HYDROXY GROUP TO PRODUCE A -KETO GROUP It was found that the addition of the methylene group to i the 6-chloro or 6-fiuoro starting product took place at the double bond between the carbon atoms 6 and 7, even if the starting product contains a double bond between the carbon atoms 1 and 2.

Furthermore, it was found that the attached methylene group, always occupies the [i-position, whereas the R substituent turns to the a-position when the reagent attacks the 6,7-double bond. These results were, in view of the literature reports concerning the addition of a methylene group to normal steroids, very surprising (Krakower, G. W. and Van Dine, H. A., The Synthesis of Steroidal Cyclopropano Ketones, Journal of Organic Chemistry, 31, 3467-3573 (1966)).

The compounds according to the invention may be worked up to pharmaceutical or veterinarian preparations in the usual way. Thus injection liquids may be produced by dissolving a methylene chloride solution of an active compound in arachid oil and by evaporating methylene chloride subsequently. Suppositaria may be produced by mixing intimately an active compound with an ester of a higher aliphatic alcohol and a higher carboxylic acid, e.g. with carbowaxes or with cacao-butter or with a mixture of gelatine and glycerol. Further the inventive product may be worked up in tablets using the usual fillers such as starch or binders or lubricants, for example magnesium stearate, carboxy methylcellulose and the like.

The invention may be further illustrated by the following examples.

EXAMPLE 1 6 ,GJB-methylene-20,8-hydroxy-9fl, 1 0a-pregn-4-en-3-one To a solution of 6 g. of trimethylsulphoxonium iodide in 60 ml. of dimethyl sulphoxide 0.7 g. of sodium hydride was added. After stirring for 75 minutes at room temperature the mixture was filtered and the filtrate was added to a solution of 3 g. of 20B-hydroxy-9fl,10a-pregna-4,6-dien- 3-one in 40 ml. of dimethylsulfoxide. The solution was allowed to stand at room temperature for 2.5 days and then poured into ice-water. The steroid material was extracted with methylene chloride. After usual work-up and evaporation of the solvents, the residue was chromatographed on silicagel to yield 1.9 g. of 613,7B-methylene- 20,8-hydroxy-9fi,10a-pregn-4-en-3-one with M.P. 128.5- 130 C., [a] =300 C. and s). 295.5 Nm.:15.500.

EXAMPLE II 6fi,7,B-methylene-9,8,10ot-pregn-4-ene-3,20 dione To a solution of 1.44 g. of 6B,7fl-methylene-20-hydroxy- 9fi,l0a-pregn-4-en-3-one in 150 ml. of acetone was added dropwise at a temperature between 0 and -5 C., 2.9 ml. of an 8 N aqueous solution of chromic acid (67 g. of

CrO and 58 ml. of concentrated sulphuric acid dissolved in water to a final volume of 250 ml. After additional stirring for 3 minutes the reaction mixture was diluted with water and worked up. The nearly pure =6a,7 8-methylene- 9B,10a-pregn-4-ene-3,20-dione was recrystallized from methylene chloride/aceton to yield an analytically pure sample with M.P. 210.5-212 C., [a] =-l89 and 6% 259.5 Nm.:15.500.

EXAMPLE III 6,6,7 8-methylene-9fi,10a-pregn-4-ene-3,20-dione According to the method described in Example I 65,75- methylene 95,100; pregn-4-ene-3,20-dione was prepared from 9 6,l0a-pregn-4,6-diene-3,20-dione. After chromatography and recrystallization the compound melted at 210.5212 C.

EXAMPLE IV Got-chloro-6fl,7 3-methylene-9;8,10a-pregn-4-ene- 3,20-dione To a solution of 4 g. of trimethylsulphoxonium iodide .in ml. of dimethyl sulphoxide 540 ml. of sodium hydride (1080 mg.) of dispersion in oil (50%) were added. After stirring for 45 minutes at 20 C. a solution of 4 g. dride (1080 mg.) of dispersion in oil (50%) were added. of tetrahydrofuran was added. The mixture was stirred for 35 minutes at 20 C. in a nitrogen atmosphere and decomposed by the addition of ethanol and water. The steroid material was extracted with benzene. The benzene extract was washed with water. After drying and evaporation of the solvents, the residue was chromatographed on silicagel to yield 1.5 g. of 6a-chloro-6,7-methylene-9p,10apregn 4 ene 3,20-dione with M.P. 188188.5 C., [u] :+4.5 and at 257 Nm.=10.400.

EXAMPLE V 6a-chloro-6B,7 ,B-rnethylene-9 S,10a-pregan-1,4-

diene-3,20-dione To a solution of 3.1 g. of trimethylsulphoxonium iodide in 37.5 ml. of dimethyl sulfoxide 0.37 g. of sodium hydride was added. After stirring for 2 hours at room temperature in a nitrogen atmosphere the mixture was filtered and the filtrate was added to a solution of 3.1 g. of -6-ch1oro- 9,10-pregna-1,4,6-triene-3,20-dione in 125 ml. of dimethyl sulphoxide. The solution was allowed to stand at 17 C. for 2 hours and then poured into ice-water. The steroid material was extracted with methylene chloride. After usual work-up and evaporation of the solvents, the residue was chromatographed on silicagel to yield 6-chloro-6B- methylene 9B,10-pregna-1,4-diene-3,20-dione with M.P. 157-159 0., EA 244 Nm.=14.000.

EXAMPLE VI Get-chloro-65,7/3-methylene-9/3,1Oaregan-IA-diene- 3,20-dione To a solution of 3 g. of 6-chloro-6B,7;8-methylene- 9B,l0a-pregn-4-ene-3,20-dione and 27 g. of D.D.Q. in 200 ml. of dioxan, 1.5 ml. of a solution of anhydrous hydrogen chloride in dioxan (133 mg./ml.) were added and the mixture was allowed to stand at room temperature for minutes. Then 5 g. of sodium-bicarbonate were added and the mixture was stirred until the solution became neutral. After filtration, the filtrate was heated under reflux for 90 minutes and then most of the dioxan was removed under reduced pressure. To the residue 300 ml. of N sodium hydroxide were added and the mixture was extracted with methylene chloride. After usual work-up 6-chloro-6fl, 7,3- methylene 9B,lOaregna-1,4-diene-3,20-dione was obtained with M.P. 157159 C.

EXAMPLE VII 65,7/3-methylene-9fi,loot-pregnal ,4-diene-3,20-dione According to the method described under Example VI, 6/3,7/3 methylene-9,8,lOa-pregna-l,4-diene-3,20-dione was synthesized from 65,7,8-methylene-9fi,l0a-pregna-4-ene-3, 20-dione.

EXAMPLE VIII 6,8,7fi-methylene-17B-hydroxy-9fi,10m-androst-4-en-3-one According to the method, described in Example I, 65.75- methylene 17/8 hydroxy-9,8,l0ot-androst-4-en-3-one was prepared from 17B-hydroxy-95,lOu-androsta-4,6-dien-3- one. The compound melted at 116.5-118" C. after resolidification in the capillary tube at l37.5-139 C., [a] =300 C. and eh 259.5 Nm.=l5.300.

EXAMPLE IX 6 a-chloro-6,8,7fl-methylene-17 B-hydroxy-9fi,1()aandrost-4-en-3-one According to the method described in Example IV, 60- chloro-6 ,7-methylene-17,8-hydroxy 95,10u androst-4-en- 3-one was prepared starting from 6-chloro-17fl-hydroxy- 9,8,10u-androsta-4,6-dien-3-one or its acetate. The compound melted at 163 164" C., [m] 6'9 and 61\ 255.5 Nm.=1 0.000.

EXAMPLE X 6a-chloro-6,7-methylene-17B-hydroxy-9B,10a-androsta- 1,4-dien-3-one l7 acetate In accordance with the method described in Example V, 6-chloro-17B-hydroxy 95,10 androsta-1,4,6-trien-3- one l7-acetate was converted into 6a-chloro-6,7-rnethylene-17fl-hydroxy 9,3,10m androsta-1,4-dien-3-one 17- acetate (after reacetylation) with M.P. 131-133" C. and ex 244 Nm.=14.000.

EXAMPLE XI 6,8,75-methylene-17B-hydroxy-9fi,10a-androst-4-en- 3-one 17-phenylpropionate 65,7,8-methylene 17B hydroxy-9B,1 u-androst-4-en- 3-one as described in Example VIII was esterified with phenylpropionyl chloride in the presence of pyridine to the corresponding 17-phenylpropionate compound.

EXAMPLE XII 6a-fluoro-6p,Iii-methylene-17B-hydroxy-913,10rx-androst- 4-en-3-0ne 17-acetate To a solution of 1 g. of trimethylsulphoxonium iodide in 20 ml. of dimethylsulphoxide 110 mg. of sodium hydride were added. After stirring for 30 minutes at 20 C., 1 g. of powdered 6 fluoro-17fi-hydroxy-9/i,10a-androsta-4,6- diene-3-one 17-acetate was added. The mixture was stirred for 2 hours at 20 C. and then worked up. The residue obtainedafter evaporation of the solvents from the dried extract was reacylated with acetic anhydride in the presence of pyridine. Usual work-up gave after chromatography and recrystallization from petroleum ether-ether 6ot-fiuoro 6,7 methylene-17,8-hydroxy-9B,lOa-androst- 4-en-3-one 17-acetate with MP. 112.5-113 C.

EXAMPLE XIII 2 g. of 6a-chloro-6fi,7fl-methylene-9',8,10a-pregn-4-ene- 3,20-dione were dissolved in chloroform, which solution was mixed homogenously with 194 g. of lactose. The mixture was dried at 40 C. during 1 hour. The mixture was wettened with a %-ic aqueous solution of 2 g. of gelatine and subsequently ground through a 20 mesh sieve. The mixture was dried at 40 C. during 24 hours, whereupon the granules were ground through a 20' mesh sieve. The mixture was weighed and then had added to it proportional amounts of talcum venetum and magnesium stearate in amounts of optimal 25 mg. and 2 mg. respectively. The resulting mixture was homogenized and worked up to tablets of 225 mg. each.

EXAMPLE XIV Injection liquids of 6fl,7fi-methylcne-9fl,l0u-pregn-4- ene-3,20-dione (active ingredient) were made as follows.

in which formula R represents a single or double bond between the carbon atoms 1 and 2,

R represents a hydrogen, a chloro or a fluoro atom and R represents a hydroxyl, esterified hydroxyl, acetyl or a CHOHCH group.

2. A compound of claim 1 of the formula I on. on. o=o

3. A compound of claim 1 of the formula o1 CH2 4. A compound of claim 1 of the formula 5. A compound of claim 1 of the formula 9. A compound of claim 1 of the formula 6. A compound of claim 1 of the formula 10. A compound of claim 1 of the formula CH3 CH3 0110K 7. A compound of claim 1 of the formula References Cited UNITED STATES PATENTS 555 555 999 333 4 3 000 666 222 r Im .m m a a "1 m t et y mw m nkm .m w w n RmB 5009 m 666 999 N 111 9% M F Z37 A 967 7 Y 0% 8 R 903 N AA E 333 H 5 3 H Q 0 US. Cl. X.R.

CH3 J;

Patent No. 3,539,599 119) Dated Novcmbcr 1O, ].97(

Inventor-(s) IIARMAN VAN KAMP It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Coluinn 9, claim 6, change the formula to read as follows Colpmn 9, claim 7, change the formula to read as follows:

CH 3 OH Signed and sealed this day of June 1971.

(SEAL) Attest:

EDWARD M. FLETCHER,JR. WILLlAM E. SCI-IUYLER, JR. 

